Hepatocyte growth factor (HGF) is a powerful mitogen which stimulates the hepatocyte proliferation. The single receptor for HGF, c-Met, is a transmembrane protein encoded by proto-oncogene c-Met. HGF activates c-Met, which results in the cascade activation by the signal transduction pathway, such as ras/mitogen-activated protein (MAP) kinase pathway, and phosphatidylinositol 3-kinase/protein kinase B pathway. A series of biological effects, such as scattering, cell movement, invasion, cell migration and eventual metastasis, occur in cells.
The human HGF gene is located on the long arm of chromosome 7 (7q21.1), has about 70 kb, and comprises 18 extrons and 17 introns. HGF is produced mainly from interstitial cells. The mature HGF has a molecular weight of 9.0×104. An alpha chain of 6.0×104 and a beta chain of 3.0×104 are connected by a disulfide linkage to form a heterodimer. The alpha chain is in a short hairpin structure and has an N-terminal region in which 4 Kringle domains are connected. The hairpin structure in the N-terminal region and the structure of its first two Kringle domains are essential for HGF to perform its biological effect. The beta chain has a serine protease-like structure, but has no catalytic activity of the protease. However, the beta chain is a prerequisite for HGF to perform its biological activity.
The human c-Met gene is located on the long arm of chromosome 7 (7q31), has about 110 kb, and comprises 21 extrons. In a mature c-Met, an alpha subunit of 5.0×104 and a beta subunit of 1.4×105 form a heterodimer. The alpha subunit is located on the exocellular part. The beta subunit includes the exocellular region, the transmembrane region and the intracellular region. The alpha subunit and the exocellular region of the beta subunit serve as the ligand recognition site and incorporate HGF. The intracellular region has a tyrosine kinase activity, and is a site where several signaling molecules, interact.
The HGF/c-Met signal transducting path is widely present in a variety of cells, and has a significant physiological adjustment effect on the growth and development of tissues and organs. However, the over-expression of HGF or c-Met in cells generally results in the invasion and metabasis of tumor cells.
The HGF/c-Met signal system is closely relevant to the invasion and metabasis of tumor cells. When stably transfecting cDNA of HGF to low metastatic cell line SMMC and comparing the cell growth and the cell mobility before and after the transfection, the results show that the high expression of HGF in the hepatoma carcinoma cells can promote the growth, invasion and metabasis of hepatoma carcinoma cells. It is found by Miura, at al. that the invasion of hepatoma carcinoma cell line AH109A is mediated by the paracrine secretion and autocrine of HGF. In the poorly differentiated tumors and the recurrent patients having the early primary hepatocellular carcinoma, c-Met is in an over-expression.
The down-regulation or the abnormal regulation of Met and/or HGF, the over-expression of Met and the mutation of Met are all relevant to the uncontrolled cell proliferation and survival. These factors occur in the early stage of tumors and play a key role in the invasion, growth and metabasis of tumor cells. The over-expression of Met and HGF are relevant to poor prognosis and diagnosis. Up to now, much evidence demonstrates that HGF is acting as a regulator in the cancer occurrence, invasion and metabasis. In the mouse model of tumor xenograft, inhibition of Met results in the tumor growth slowdown, which is because the specific antibody of c-Met has been expressed to block the combination of HGF and c-Met. Moreover, c-Met is also over-expressed in the cells of nonsmall-cell lung cancer and small-cell lung cancer, lung cancer, breast cancer, colon cancer and prostatic carcinoma. Since c-Met appears to play an important role in tumor formation of several tumors, several inhibition strategies have been applied to therapeutically target the receptor tyrosine kinase, which also makes Met the important target in the development of anticancer drugs.
Modulation of the HGF/c-met signaling pathway may be effected by regulating binding of HGF beta chain to c-Met. In particular embodiments, the zymogen-like form of HGF beta mutant was shown to bind c-Met with 14-fold lower affinity than the wild-type serine protease-like form, suggesting that optimal interactions result from conformational changes upon cleavage of the single-chain form (US 2005/0037431). Extensive mutagenesis of the HGF beta region corresponding to the active site and activation domain of serine proteases showed that 17 of the 38 purified two-chain HGF mutants resulted in impaired cell migration or c-Met phosphorylation, without loss in Met binding. However, the reduced biological activities were well correlated with reduced Met binding of corresponding mutants of HGF beta itself in assays eliminating dominant alpha-chain binding contributions (CN200780029441.2).
Based on the relevant prior art references, the present inventors design and synthesize a series of quinoline derivatives comprising 1,2,4-triazine-3,5-dione. By an in-vitro activity screen, it is shown that this series of compounds have an anti-tumor activity.
Contents of Invention
The present invention relates to a quinoline compound comprising 1,2,4-triazine-3,5-dione represented by general formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
wherein,    X is O, S, NH, NCH3;    Y is halogen;    n is an integral between 2 and 6;    R1 and R2 are identical or different, and independently and respectively selected from the group consisting of hydrogen, C1-C10alkyl, C3-C7cycloalkyl, C2-C10alkenyl and C2-C10alkynyl, which can be optionally substituted by 1-3 identical or different R4 substituents; or R1 and R2 together with the nitrogen atom bonded thereto form 5-10 membered heterocyclyl or 5-10 membered heteroaryl, said heterocyclyl and heteroaryl optionally contain 1-4 hetero atoms selected from N, O and S besides the nitrogen atom bonded to R1 and R2, said heterocyclyl optionally comprises 1 or 2 carbon-carbon double bonds besides the nitrogen atom bonded to R1 and R2, said heterocyclyl and heteroaryl are optionally substituted by 1-3 identical or different R4 substituents;    R4 is C1-C6alkyl, hydroxy, cyano, carboxyl, an ester group;    R3 is H, C3-C6cycloalkyl, allyl, —CH2-Ar1;    Ar1 is phenyl, and optionally substituted by 1-3 identical or different R5 substituents;    Ar is C6-C10aryl, 5-10 membered heteroaryl, wherein said heteroaryl contains 1-3 hetero atoms selected from N, O and S, and Ar is optionally substituted by 1-3 identical or different R5 substituents;    R5 is hydroxy, halogen, nitro, amino, cyano, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)alkoxyl, (C1-C6)alkyl or (C1-C6)alkoxyl optionally substituted by hydroxy, amino or halogen, mono or di[(C1-C6)alkyl] substituted amino, (C1-C6)alkylamido, a carboxyl radical which is free, salified, esterified or amidated, (C1-C6)alkylsulfinyl, sulfonyl, (C1-C6)alkoxyl, (C1-C6)alkyl, (C1-C6)alkylacyl, carbamoyl, mono or di(C1-C6alkyl) substituted carbamoyl, (C1-C3)alkylenedioxy.
The present invention preferably relates to a quinoline compound comprising 1,2,4-triazine-3,5-dione represented by general formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
wherein,
    X is O, S;    Y is halogen;    n is an integral between 2 and 6;    R1 and R2 are identical or different, and independently and respectively selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, which can be optionally substituted by 1-3 identical or different R4 substituents;or R1 and R2 together with the nitrogen atom bonded thereto form 5-10 membered heterocyclyl, said heterocyclyl optionally contains 1-4 hetero atoms selected from N, O and S besides the nitrogen atom bonded to R1 and R2, said heterocyclyl optionally comprises 1 or 2 carbon-carbon double bonds or triple bonds besides the nitrogen atom bonded to R1 and R2, said heterocyclyl is optionally substituted by 1-3 identical or different R4 substituents.    R4 is C1-C4alkyl, C1-C4alkoxyl, halo, hydroxy, cyano, carboxyl, an ester group;    R3 is H, C1-C4alkyl, C3-C6cycloalkyl, allyl, benzyl;    Ar is C6-C10aryl, 5-10 membered heteroaryl, wherein said heteroaryl contains 1-3 hetero atoms selected from N, O and S, and Ar is optionally substituted by 1-3 identical or different R5 substituents;    R5 is hydroxy, halogen, nitro, amino, cyano, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)alkoxyl, (C1-C6)alkyl or (C1-C6)alkoxyl optionally substituted by hydroxy, amino or halogen, mono or di[(C1-C6)alkyl] substituted amino, (C1-C6)alkylamido, a carboxyl radical which is free, salified, esterified or amidated, (C1-C6)alkylsulfinyl, sulfonyl, (C1-C6)alkoxyl, (C1-C6)alkyl, (C1-C6)alkylacyl, carbamoyl, mono or di(C1-C6alkyl) substituted carbamoyl, (C1-C3)alkylenedioxy.
Furthermore, the present invention preferably relates to a quinoline compound comprising 1,2,4-triazine-3,5-dione represented by general formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
wherein,
    X is O;    Y is F;    n is an integral between 2 and 4;    R1 and R2 together with the nitrogen atom bonded thereto form 5-6 membered heterocyclyl, said heterocyclyl optionally contains 1-3 hetero atoms selected from N, O and S besides the nitrogen atom bonded to R1 and R2, said heterocyclyl optionally comprises 1 or 2 carbon-carbon double bonds or triple bonds besides the nitrogen atom bonded to R1 and R2, said heterocyclyl is optionally substituted by 1-3 identical or different R4 substituents;    R4 is C3-C4alkyl, C1-C4alkoxyl, halo, hydroxy, cyano, carboxyl, an ester group;    R3 is H, C1-C4alkyl, allyl, benzyl;    Ar is phenyl, 5-6 membered heteroaryl, wherein said heteroaryl contains 1-3 hetero atoms selected from N, O and S, and Ar is optionally substituted by 1-3 identical or different R5 substituents;    R5 is hydroxy, halogen, nitro, amino, cyano, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)alkoxyl, (C1-C6)alkyl or (C1-C6)alkoxyl optionally substituted by hydroxy, amino or halogen, mono or di[(C1-C6)alkyl] substituted amino, (C1-C6)alkylamido, a carboxyl radical which is free, salified, esterified or amidated, (C1-C6)alkylsulfinyl, sulfonyl, (C1-C6)alkoxyl, (C1-C6)alkyl, (C1-C6)alkylacyl, carbamoyl, mono or di(C1-C6alkyl) substituted carbamoyl, (C1-C3)alkylenedioxy,
The present invention particularly preferably relates to a quinoline compound comprising 1,2,4-triazine-3,5-dione represented by general formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
wherein,
    X is O;    Y is F;    n is an integral between 2 and 4, preferably 3;    R1 and R2 together with the nitrogen atom bonded thereto form 5-6 membered saturated heterocyclyl, said saturated heterocyclyl optionally contains one hetero atom selected from N, O and S besides the nitrogen atom bonded to R1 and R2, and is optionally substituted by 1-3 identical or different R4 substituents; particularly preferably R1 and R2 together with the nitrogen atom bonded thereto form 1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl, 1-piperazinyl, 4-methyl-1-piperidinyl, 1-pyrrolidyl, 4-thiomorpholinyl;    R4 is C1-C4alkyl;    R3 is hydrogen, C1-C4alkyl, preferably methyl, ethyl, propyl, butyl and allyl; more preferably methyl    Ar is phenyl, pyridinyl, pyrrolyl, furyl, thienyl, preferably phenyl, and Ar is optionally substituted by 1-3 identical or different R5 substituents.
R5 is hydroxy, halogen, nitro, amino, cyano, (C1-C6)alkyl, (C1-C6)alkenyl, (C1-C6)alkynyl, (C1-C6)alkoxyl, (C1-C6)alkyl or (C1-C6)alkoxyl optionally substituted by hydroxy, amino or halogen, mono or di[(C1-C6)alkyl] substituted amino, (C1-C6)alkylamido, a carboxyl radical which is free, salified, esterified or amidated, (C1-C6)alkylsulfinyl, sulfonyl, (C1-C6)alkoxyl, (C1-C6)alkyl, (C1-C6)alkylacyl, carbamoyl, mono or di(C1-C6alkyl) substituted carbamoyl, (C1-C3)alkylenedioxy;    R5 is preferably halogen, (C1-C4)alkyl, (C1-C4)alkoxyl, (C1-C4)alkyl or (C1-C4)alkoxyl optionally substituted by halogen, mono or di(C1-C6alkyl) substituted amino, (C1-C4)alkoxyl(C7-C4)alkyl, (C1-C6)alkylacyl, carbamoyl, mono or di(C1-C6alkyl) substituted carbamoyl, (C1-C3)alkylenedioxy.
R5 is more preferably halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy; R5 is particularly preferably fluoro, chloro, trifluoromethyl and methyl.
The present compound of general formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof is more preferably selected from the group consisting of the following compounds, which however do not imply any limitation to the scope of the present invention:    N-[3-fluoro-4-[6-methoxy-7-[3-(4-morpholinyl)propyloxy]quinolin-4-oxy]phenyl]-2-phenyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-morpholinyl)propyloxy]quinolin-4-oxy]phenyl]-2-phenyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-phenyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-pyrrolidyl)propyloxy]quinolin-4-oxy]phenyl]-2-phenyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperazinyl)propyloxy]quinolin-4-oxy]phenyl]-2-phenyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-morpholinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-fluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-fluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-pyrrolidyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-fluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-fluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperazinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-fluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-morpholinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(3,4-difluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-pyrrolidyl)propyloxy]quinolin-4-oxy]phenyl]-2-(3,4-difluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(3,4-difluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperazinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(3,4-difluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(3,4-difluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-morpholinyl)propyloxy]quinolin-4-oxy]phenyl]-4-methyl-3,5-dicarbonyl-2-(3-trifluoromethylphenyl)-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-pyrrolidyl)propyloxy]quinolin-4-oxy]phenyl]-2-(3-trifluoromethylphenyl)-4-methyl-3,5-dicarbonyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(3-trifluoromethylphenyl)-4-methyl-3,5-dicarbonyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperazinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(3-trifluoromethylphenyl)-4-methyl-3,5-dicarbonyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(3-trifluoromethylphenyl)-4-methyl-3,5-dicarbonyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-morpholinyl)propyloxy)quinolin-4-oxy]phenyl]-2-(3-fluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(3-fluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-pyrrolidyl)propyloxy]quinolin-4-oxy]phenyl]-2-(3-fluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperazinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(3-fluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-tri azine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(3-fluorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-morpholinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-chlorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-chlorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-pyrrolidyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-chlorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-chlorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperazinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-chlorophenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(morpholin-1-yl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-methylphenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-pyrrolidyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-methylphenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-methylphenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperazinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-methylphenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-methylphenyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(4-morpholinyl)propyloxy]quinolin-4-oxy]phenyl]-2-phenyl-4-butyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(1-pyrrolidyl)propyloxy]quinolin-4-oxy]phenyl]-2-phenyl-4-butyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-tri azine-6-carboxamide;    N-[3fluoro-4-[7-methoxy-6-[3-(4-methyl-1-piperazinyl)propyloxy]quinolin-4-oxy]phenyl]-2-phenyl-4-butyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(4-methyl-1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(2-trifluoromethylphenyl)-4-butyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(4-morpholinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(2-trifluoromethylphenyl)-4-butyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(1-pyrrolidyl)propyloxy]quinolin-4-oxy]phenyl]-2-(2-trifluoromethylphenyl)-4-butyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(4-methyl-1-piperazinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(2-trifluoromethylphenyl)-4-butyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(4-methyl-1-piperazinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-chlorophenyl)-4-allyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(4-methyl-1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-fluorophenyl)-4-allyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[4-methoxy-6-[3-(4-morpholinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(2-trifluoromethylphenyl)-4-allyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(2-trifluoromethylphenyl)-4-allyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-phenyl-4-allyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(4-methyl-1-piperidinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(4-chlorophenyl)-4-allyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(1-pyrrolidyl)propyloxy]quinolin-4-oxy]phenyl]-2-(2-fluorophenyl)-4-allyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(4-morpholinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(2-fluorophenyl)-4-allyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(4-morpholinyl)propyloxy]quinolin 4-oxy]phenyl]-2-(3-fluorophenyl)-4-allyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[7-methoxy-6-[3-(4-morpholinyl)propyloxy]quinolin-4-oxy]phenyl]-2-(2-methylphenyl)-4-allyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-pyrrolidyl)propyloxy]quinolin]-4-oxy]phenyl]-2-(4-chlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-morpholinyl)propyloxy]quinolin]-4-oxy]phenyl]-2-(4-chlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-piperidinyl)propyloxy]quinolin]-4-oxy]phenyl]-2-(4-chlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperazinyl)propyloxy]quinolin]-4-oxy]phenyl]-2-(4-chlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-pyrrolidyl)propyloxy]quinolin]-4-oxy]phenyl]-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-morpholinyl)propyloxy]quinolin]-4-oxy]phenyl]-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-piperidinyl)propyloxy]quinolin]-4-oxy]phenyl]-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperazinyl)propyloxy]quinolin]-4-oxy]phenyl]-2-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(1-piperidinyl)propyloxy]quinolin]-4-oxy]phenyl]-2-(3-trifluoromethylphenyl)-4-benzyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;    N-[3-fluoro-4-[6-methoxy-7-[3-(4-methyl-1-piperazinyl)propyloxy]quinolin]-4-oxy]phenyl]-2-(3-trifluoromethylphenyl)-4-benzyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide;
The following synthesis schemes will illustrate the preparation of the present compounds of general formula (I) of the present invention, wherein all starting materials can be prepared by the methods depicted in the schemes or the methods well known to one of ordinary skill in the organic chemistry art, or are commercially available. All of the final compounds of the present invention are prepared by the methods depicted in the schemes or similar methods, and these methods are well known to one of ordinary skill in the organic chemistry art. All variable factors as involved in these schemes are defined as follows or defined as in claims. The present compounds of general formula (I) of the present invention can be prepared according to the method in Scheme 1 by the substitution reaction from Intermediates A and C, wherein the variants R1, R2, n, X, Y, R3 and R5 are defined as in the claims.

The synthesis route for Intermediate A is shown in Scheme 2, wherein the variants are defined as in the claims.

The synthesis route for Intermediate C is shown in Scheme 3, wherein R3 is C1-C4alkyl, C3-C6cycloalkyl, allyl, —CH2—Ar1; and the other variants are defined as in claims.

In case that R3 is H, Intermediate C can be obtained by directly hydrolyzing Intermediate c with an acid to produce Intermediate e, and then reacting the obtained Intermediate e and thionyl chloride.